Patent TW-355707-B (TW)
Title: Method for preparing N, N'-disubstituted cyclic ureas
Inventor: SMYSER THOMAS EDGAR
IPC: C07D243/04
Filed: 1996-07-30
Granted: 1999-04-11
Abstract: A method for preparing compound of formula (IV), where R4 and R7 are selected respectively from: C1-C8 alkyl substituted by 0-1 R11; R11 is selected from one or more groups below: phenyl, C2-C4 alkenyl, -OR13, C5-C14 carbon cyclic residual group substituted by 0-3 R12; 5 to 6-membered heterocyclic system selected from pyridyl, pyrimidinyl, trihydrazine, furyl, thienyl, pyrrolyl, pyrazinyl, imidazolyl, tetraazolyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, oxazolyl; the heterocyclic system is substituted by 0-2 R12; R12, when having a substitution group on the carbon atom, is selected from one or more of the following groups: halogen, -OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propyloxy, butyloxy, -NH2, -N(CH3)2, CF3 and -CF2CF3; R12, when having a substitution group on the nitrogen atom, is selected from one or more of the following groups: methyl, ethyl, propyl and butyl; R13 is individually selected from H, phenyl, benzyl, C1-C6 alkyl, amine protecting group (when R13 and N are connected); and hydroxy or carboxyl protecting group (when R13 are connected to O); and C1-C6 alkyl substituted by 0-3 groups selected from -OH, C1-C4 alkoxy, halogen; R20 and R21 are individually selected from: C1-C6 alkyl, C3-C6 alkoxyalkyl, and hydroxy protecting group; R20 and R21 optionally form with adjacent oxygen atom one of the following groups: m is 0, 1 or 2; R22 is selected from the following: C1-C8 alkyl substituted by 0-3 R31; C2-C8 alkenyl substituted by 0-3 R31; C2-C8 alkynyl substituted by 0-3 R31; phenyl substituted by 0-5 R32; C3-C14 carbon cyclic system selected from 0-5 R32; and 5- to 10-membered heterocylic system selected from the composition of the following groups: thiazole, isoquinoline, quinoline, indolyl, thienyl[2,3-c]pyrazinyl and thienyl[3,2-c]pyrazinyl; the heterocyclic system is substituted by 0-2 R32 R23=R22; R31 is selected from one or more of the following groups: -OH, C1-C4 alkoxy, ketone, halogen, -NR13R14, -CO2H, -CO2CH3, -OC(=O)R13, -OC(=O)NHCH3, C1-C4 alkyl, C2-C4 alkenyl, nitro, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, C3-C6 cycloalkoxy, or C5-C14 carbon cyclic residual group substituted by 0-5 R32; or 5 to 10-membered heterocyclic system selected from pyridyl, pyrimidinyl, trihydrazine, furyl, thienyl, pyrrolyl, pyrazinyl, imidazolyl, tetraazolyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, oxazolyl, phenylimidazolyl, benzotriazolyl, indole, benzooxazolinyl, benzooaxazolyl; R32, when having one substitution group on carbon atom, is selected from one or more of the following groups: phenyethyl, phenyloxy, C3-C10 cycloalkyl, C3-C6 cycloalkylmethyl, hydrazide, C2-C6 alkoxyalkyl, C1-C4 alkylcarbonyloxy, benzyloxy, halogen, -CO2R13, sulfuryl, cyano, (formulae), phenyl, C1-C4 haloalkyl, or (formulae); or (formulae); or C1-C4 alkoxy, substituted by 0-4 of the following groups: R11, C3-C6 cycloalkyl, -CO2R13, -C(=O)NR13R14, -NR13R14 or OH; or C1-C4 alkyl, substituted by 0-4 of the following groups: or C2-C4 alkenyl substituted by 0-2 R11; or C2-C4 alkynyl substituted by 0-2 R11; 5 to 6-membered heterocyclic system selected from pyridyl, pyrimidinyl, trihydrazine, furyl, thienyl, pyrrolyl, pyrazinyl, imidazolyl, tetraazolyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, oxazolyl; the heterocyclic system is substituted by 0-2 R12; p is 0, 1 or 2; n is 1 or 2; and R32, when having a substitution group on the nitrogen atom, is selected from one or more of the following groups: phenyl, benzyl, phenyethyl, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, -CH2NR13R14, C2-C6 alkoxyalkyl, C1-C4 alkoxycarbonyl, -CO2H, C1-C4 alkylcarbonyl; with the proviso that the reactive R4, R7, R22 and R23 in steps (1) and (2) are protected by protecting groups which are obtained by removed or converted into the functional group desired by the following step (3): step (1): reacting amine of formula (I) in appropriate sovlent with at least 2 mole equivalent of aldehydeR22-CHO or R23-CHO for a sufficient period of time in the presence of 1mole equivalent of acid and at least 2 mole equivalent of appropriate imide reduction agent to form compound of formula (II): step (2): reacting the secondary amide of formula (II) in appropriate non-proton solvent with at least 0.3 mole equivalent of cyclization agent for a sufficient period of time in the presence of at least 1mole equivalent of hindered amino base under proper temperature to form compound of formula (III); and step (3): reacting the cyclic urea of formula (III) in suitable solvent with one or more reactants and/or condition, and/or combination for a sufficient period oft ime to convert R20 and R21 into H, and remove the protection of R4, R7, R22 and R23 or converting them into the functional group desired to form compound (IV).